We reported the identification of highly conserved homologous regions located in the carboxy terminous of the HIV 1 gp4l-envelope (837-844), and the amino-terminal of the beta chain of all human class II antigens (aa 19-25). Murine monoclonal antibodies, raised against synthetic peptides from these homologous regions, bound not only to the isolated peptides, but.also to the "native" gpl6O and class II molecules. In our study of sera from HIV 1 infected patients, we found that about a third of patients at different stages of the disease, produced such cross reactive antibodies. In various functional assays, it was demonstrated that such antibodies can severely interfere with normal proliferative responses of CD4 bearing cells to tetanus toxoid and allostimulation. Furthermore, such antibodies can lead to killing of class II expressing uninfected cells by Antibody Mediated Cellular Cytotoxicity (ADCC). It was also established that among asymptomatic patients, those producing the crossreactive antibodies show early immunodeficiency of their CD4 bearing cells, in that they do not respond normally to recall antigens, such as influenza, tetanus toxoid, etc. Thus, the "Molecular Mimicry" between HIV 1 and HLA class II antigens may lead to the generation of autoantibodies in HIV 1 infected individuals that may contribute to the early functional impairment of CD4+ T cells observed in many HIV 1 infected individuals. Currently, we are testing a cohort of HIV 1 infected hemophiliacs. In addition, a special emphasis is given to screening of sera from vaccinated chimps and humans to determine if various vaccine which are currently in preclinical and Phase I studies can potentially give rise to the deleterious antibodies in otherwise healthy individuals. We are also testing the ability of peptided derived from the CD4- receptor to block in vitro infection of human cell lines with cell free HIV 1.